1. Field of the Invention
The present invention relates to butyrolactones having potential therapeutic antitumor activity. More particularly, the present invention relates to peperomin analogs and the use thereof in treating cancer.
2. Description of Related Arts
Increasing research has been devoted to developing synthetic routes to .gamma.-butyrolactones. This has been in large part due to interest in several biologically active natural products that have the .gamma.-butyrolactone moiety as a major structure feature. Examples of such biologically active natural products are peperomin, ambrosin, alantolactone, and euparotin.
These naturally occurring lactones have potential therapeutic application. However, they suffer from the problem of aqueous insolubility. Recently, a number of water-soluble ambrosin derivatives have therefore been prepared for potential use as prodrugs (See, Hejchman, et al. J. Med. Chem. 1995, 38, 3407). The water-soluble ambrosin analogs, known to possess potent antitumor activity, were prepared by reacting ambrosin with secondary amines, sodium bisulfite, or sodium dithionite via Michael addition. It is believed that after administration the Michael adducts are converted back to ambrosin by a retro-Michael mechanism.
Peperomins A, B, and C, each a lignan having unusual seco structure, were isolated from the Chinese plant Peperomia japonica Makino (Piperaceae). The aqueous and alcoholic decoctions of the whole herb are used in folk medicine for treating malignant tumors. The peperomin A, B, and C series can be regarded as 2-methyl-3-di[(substituted)phenyl]methyl .gamma.-lactone derivatives (see formula below). ##STR2## Peperomin A: R.sub.1, R.sub.2 =--OCH.sub.2 O--; R.sub.1 ', R.sub.2 '=--OCH.sub.2 O--; R.sub.3 .dbd.R.sub.3 '.dbd.OCH.sub.3
Peperomin B: R.sub.1 .dbd.R.sub.2 .dbd.OCH.sub.3 ; R.sub.1 ', R.sub.2 '=--OCH.sub.2 O-- PA1 Peperomin C: R.sub.1 .dbd.R.sub.2 .dbd.R.sub.3 .dbd.R.sub.1 '.dbd.R.sub.2 '.dbd.R.sub.3 '.dbd.OCH.sub.3
The isolation and synthesis of peperomins A, B, and C have been described (See, Chen, et al., Heterocycles, 1989, 29, 411 and Zee, et al., Journal of the Chinese Chemical Society 1990, 37, 583).
A problem encountered with current anticancer drugs, e.g., doxorubicin, is hypersensitivity towards leukemia cells versus other solid tumor cells.